Publications by authors named "Sophie Lancelot"

18 Publications

  • Page 1 of 1

PET-MRI nanoparticles imaging of blood-brain barrier damage and modulation after stroke reperfusion.

Brain Commun 2020 11;2(2):fcaa193. Epub 2020 Nov 11.

Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69000 Lyon, France.

In an acute ischaemic stroke, understanding the dynamics of blood-brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood-brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood-brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood-brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10min, respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10min in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, for both Gd-DOTA and AGuIX nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10min for Gd-DOTA and AGuIX nanoparticles, respectively. With AGuIX nanoparticles, also increased within the ischaemic growth areas, suggesting added value for AGuIX. Finally, was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A,  = 7) compared to placebo ( = 5). quantification with AGuIX nanoparticles can monitor early blood-brain barrier damage and treatment effect in ischaemic stroke after reperfusion.
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http://dx.doi.org/10.1093/braincomms/fcaa193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716090PMC
November 2020

Cluster headache: state of the art of pharmacological treatments and therapeutic perspectives.

Fundam Clin Pharmacol 2020 Dec 8. Epub 2020 Dec 8.

Lyon Neuroscience Research Center (CRNL), Université de Lyon, CNRS, INSERM, Lyon, France.

Cluster headache (CH) is the most common form of trigeminal autonomic cephalalgia. Current treatments have several limitations, and new drugs are required. This article first briefly reviews present acute and preventive treatments in CH, their mechanism of action and limitations, then describes the state of the art in recent clinical drug trials since 2015, and ends with a critique of trials in the CH field. Research is limited by lack of knowledge of pathophysiology and lack of animal models. In the past 5 years, no brand-new treatment has emerged, but promising drugs, such as CGRP(R) antibodies, are under study. According to the literature and guidelines, clinicians and researchers should be aware of many limitations in study protocols: concomitant medication, patient sample size, patients' protocol compliance, and study designs that tend to restrict patient recruitment.
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http://dx.doi.org/10.1111/fcp.12636DOI Listing
December 2020

A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.

J Cereb Blood Flow Metab 2020 May 19:271678X20921310. Epub 2020 May 19.

CREATIS, CNRS UMR-5220, INSERM U1206, Université Lyon 1, INSA Lyon Bât. Blaise Pascal, Villeurbanne, France.

Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia () based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.
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http://dx.doi.org/10.1177/0271678X20921310DOI Listing
May 2020

Change in Expression of 5-HT6 Receptor at Different Stages of Alzheimer's Disease: A Postmortem Study with the PET Radiopharmaceutical [18F]2FNQ1P.

J Alzheimers Dis 2020 ;75(4):1329-1338

Lyon Neuroscience Research Center (CRNL), Université de Lyon, CNRS, INSERM, Lyon, France.

Background: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer's disease (AD) and associated disorders.

Objective: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages.

Methods: Patients were classified according to the "ABC" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD ("High"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), "Low" (n = 18), "Int" (n = 20), and "High" (n = 15).

Results: In vitro binding assays did not show significant differences for the KD and Bmax parameters between "High" and HC groups. In vitro quantitative autoradiography showed a significant difference between the "High" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined ("Low", "Intermediate", and "High") (p = 0.011).

Conclusion: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.
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http://dx.doi.org/10.3233/JAD-191278DOI Listing
January 2020

Preclinical validation of [F]2FNQ1P as a specific PET radiotracer of 5-HT receptors in rat, pig, non-human primate and human brain tissue.

Nucl Med Biol 2020 Mar - Apr;82-83:57-63. Epub 2020 Jan 22.

Lyon Neuroscience Research Center, Université de Lyon, CNRS, INSERM, Lyon, France; Hospices Civils de Lyon, Bron, France; CERMEP Imaging Platform, Bron, France.

Introduction: The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [F]2FNQ1P, a new PET radiotracer of 5-HT receptors, in rat, pig, non-human primate and human tissues. The 5-HT receptor is one of the more recently identified serotonin receptors in central nervous system and, because of its role in memory and cognitive processes, is considered as a promising therapeutic target.

Methods: In-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat.

Results: In all species, autoradiography data revealed high binding levels of [F]2FNQ1P in cerebral regions with high 5-HT receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided K and B values of respectively 1.34 nM and 0.03 pmol·mg in rat, 0.60 nM and 0.04 pmol·mg in pig, 1.38 nM and 0.07 pmol·mg in non-human primate, and 1.39 nM and 0.15 pmol·mg in human caudate nucleus. In rat brain, the proportion of unmetabolized [F]2FNQ1P was >99% 5 min after iv injection and 89% at 40 min. The biodistribution studies found maximal radioactivity in lungs and kidneys (3.5 ± 1.2% ID/g and 2.0 ± 0.7% ID/g, respectively, 15 min post-injection).

Conclusion: These radiopharmacological data confirm that [F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT receptors and suggest that it could be used as a radiopharmaceutical in humans.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.01.006DOI Listing
January 2020

In Silico, in Vitro, and in Vivo Evaluation of New Candidates for α-Synuclein PET Imaging.

Mol Pharm 2018 08 25;15(8):3153-3166. Epub 2018 Jul 25.

Université de Lyon, Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028 , Lyon 69361 , France.

Accumulation of α-synuclein (α-syn) is a neuropathological hallmark of synucleinopathies. To date, no selective α-syn positron emission tomography (PET) radiotracer has been identified. Our objective was to develop the first original, selective, and specific α-syn PET radiotracer. Chemical design inspired from three structural families that demonstrated interesting α-syn binding characteristics was used as a starting point. Bioinformatics modeling of α-syn fibrils was then employed to select the best molecular candidates before their syntheses. An in vitro binding assay was performed to evaluate the affinity of the compounds. Radiotracer specificity and selectivity were assessed by in vitro autoradiography and in vivo PET studies in animal (rodents) models. Finally, gold standard in vitro autoradiography with patients' postmortem tissues was performed to confirm/infirm the α-syn binding characteristics. Two compounds exhibited a good brain availability and bound to α-syn and Aβ fibrils in a rat model. In contrast, no signal was observed in a mouse model of synucleinopathy. Experiments in human tissues confirmed these negative results.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00229DOI Listing
August 2018

PET imaging of the influence of physiological and pathological α-synuclein on dopaminergic and serotonergic neurotransmission in mouse models.

CNS Neurosci Ther 2019 01 20;25(1):57-68. Epub 2018 May 20.

Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.

Aims: Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of neurodegenerative synucleinopathies. This in vivo study explored glucose metabolism and dopaminergic and serotoninergic neurotransmission in KO α-syn, wild-type mice and an accelerated murine model of synucleinopathy (M83).

Methods: MicroPET acquisitions were performed in all animals aged 5-6 months using five radiotracers exploring brain glucose metabolism ([ F]FDG), dopamine neurotransmission ([ C]raclopride, [ C]PE2I) and serotonin neurotransmission ([ F]MPPF, [ C]DASB). For all radiotracers, except [ F]FDG, PET data were analyzed with a MRI-based VOI method and a voxel-based analysis.

Results: MicroPET data showed a decrease in [ C]raclopride uptake in the caudate putamen of KO α-syn mice, in comparison with M83 and WT mice, reflecting a lower concentration of D receptors. The increase in [ F]MPPF uptake in M83 vs WT and KO mice indicates overexpression of 5-HT receptors. The lack of change in dopamine and serotonin transporters in all groups suggests unchanged neuronal density.

Conclusions: This PET study highlights an effect of α-syn modulation on the expression of the D receptor, whereas aggregated α-syn leads to overexpression of 5-HT receptor, as a pathophysiological signature.
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http://dx.doi.org/10.1111/cns.12978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436587PMC
January 2019

Amyloid-Beta Radiotracer [F]BF-227 Does Not Bind to Cytoplasmic Glial Inclusions of Postmortem Multiple System Atrophy Brain Tissue.

Contrast Media Mol Imaging 2018 6;2018:9165458. Epub 2018 Feb 6.

Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.

The accumulation of aggregated alpha-synuclein (-syn) in multiple brain regions is a neuropathological hallmark of synucleinopathies. Multiple system atrophy (MSA) is a synucleinopathy characterized by the predominant cerebral accumulation of aggregated -syn as cytoplasmic glial inclusions (CGI). A premortem diagnosis tool would improve early diagnosis and help monitoring disease progression and therapeutic efficacy. One Positron Emission Tomography (PET) study suggested [C]BF-227 as a promising radiotracer for monitoring intracellular -syn deposition in MSA patients. We sought to confirm the binding of this radiotracer to -syn using state-of-the-art autoradiography. Medulla sections were obtained from 9 MSA patients and 9 controls (London Neurodegenerative Diseases Brain Bank). [F]BF-227, chemically identical to [C]BF-227, was used at nanomolar concentrations to perform autoradiography assays. Autoradiograms were superimposed on fluorescent staining from the conformational anti--syn antibody 5G4 and quantified after immunofluorescence-driven definition of regions of interest. Autoradiography showed no specific signals in MSA patients in comparison to controls despite widespread pathology detected by immunofluorescence. Autoradiography does not support a significant binding of [F]BF-227 to CGI at concentrations typically achieved in PET experiments.
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http://dx.doi.org/10.1155/2018/9165458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818909PMC
July 2019

Paraneoplastic syndrome demonstrated on Tc-HMDP bone scan.

Eur J Nucl Med Mol Imaging 2016 Nov 11;43(12):2271-2272. Epub 2016 Aug 11.

Service de Médecine Nucléaire, Hospices Civils de Lyon, Lyon, France.

A 23-year-old man, with no relevant medical history, presented with inflammatory peripheral and axial polyarthritis, wrist pain, and persistent low-grade fever for the past 4 months. A bone scintigraphy showed intense periosteal early and delayed uptake in long bones, with normal uptake in the spine, pelvis, and rib cage, and no clear focus of hypermetabolism. CT scan revealed a mediastinal mass. A biopsy of the mass demonstrated Hodgkin lymphoma with bulky disease. This paraneoplastic syndrome as the first sign of intrathoracic Hodgkin's disease is rare.
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http://dx.doi.org/10.1007/s00259-016-3471-9DOI Listing
November 2016

Binding of the PET radiotracer [¹⁸F]BF227 does not reflect the presence of alpha-synuclein aggregates in transgenic mice.

Curr Alzheimer Res 2014 ;11(10):955-60

CERMEP-Imaging Platform, 59 boulevard Pinel, Lyon, F-69003, France.

Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many neurodegenerative diseases, collectively termed synucleinopathies. There is currently no pre-mortem diagnosis tool for these diseases. Although some compounds have been described as potential ligands for α-syn aggregates, no specific PET radiotracer of aggregated α-syn is currently available. Recently, [(18)F]BF227 has been proposed as an α-syn PET radiotracer in the absence of other specific candidates. We proposed here, for the first time, to use this radiotracer in an accelerated mouse model of synucleinopathy presenting α-syn depositions in brainstem and thalamus. Our in vivo and in vitro studies showed that [(18)F]BF227 does not bind to α-syn aggregates. These results highlight the fact that [(18)F]BF227 PET has no suitable characteristics for monitoring this experimental synucleinopathy, justifying the need to develop alternative α-syn PET radiotracers.
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http://dx.doi.org/10.2174/1567205011666141107154201DOI Listing
August 2015

A multi-atlas based method for automated anatomical rat brain MRI segmentation and extraction of PET activity.

PLoS One 2014 17;9(10):e109113. Epub 2014 Oct 17.

CERMEP - Imagerie du Vivant, Lyon, France.

Introduction: Preclinical in vivo imaging requires precise and reproducible delineation of brain structures. Manual segmentation is time consuming and operator dependent. Automated segmentation as usually performed via single atlas registration fails to account for anatomo-physiological variability. We present, evaluate, and make available a multi-atlas approach for automatically segmenting rat brain MRI and extracting PET activies.

Methods: High-resolution 7T 2DT2 MR images of 12 Sprague-Dawley rat brains were manually segmented into 27-VOI label volumes using detailed protocols. Automated methods were developed with 7/12 atlas datasets, i.e. the MRIs and their associated label volumes. MRIs were registered to a common space, where an MRI template and a maximum probability atlas were created. Three automated methods were tested: 1/registering individual MRIs to the template, and using a single atlas (SA), 2/using the maximum probability atlas (MP), and 3/registering the MRIs from the multi-atlas dataset to an individual MRI, propagating the label volumes and fusing them in individual MRI space (propagation & fusion, PF). Evaluation was performed on the five remaining rats which additionally underwent [18F]FDG PET. Automated and manual segmentations were compared for morphometric performance (assessed by comparing volume bias and Dice overlap index) and functional performance (evaluated by comparing extracted PET measures).

Results: Only the SA method showed volume bias. Dice indices were significantly different between methods (PF>MP>SA). PET regional measures were more accurate with multi-atlas methods than with SA method.

Conclusions: Multi-atlas methods outperform SA for automated anatomical brain segmentation and PET measure's extraction. They perform comparably to manual segmentation for FDG-PET quantification. Multi-atlas methods are suitable for rapid reproducible VOI analyses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109113PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201469PMC
July 2015

Chemotherapy-related gallbladder visualization in a 99mTc-HMDP SPECT/CT bone scan.

Clin Nucl Med 2013 Oct;38(10):829-31

From the *Department of Nuclear Medicine Lumen, and University Claude Bernard Lyon, Lyon; †INSERM U1028-CNRS UMRS5292, Lyon; and ‡EA 3738, Faculté Charles Mérieux Lyon Sud, Lyon, France.

Nonosseous uptakes are occasionally found on bone scintigraphy. Most of them are easily explained by current pathophysiological mechanisms (metastatic calcifications, metabolic process, or extravascular accumulation of radiopharmaceutical) or current artifacts. Other unusual findings are still unexplained. We report 1 didactic case of incidental gallbladder uptake on bone scan. Additional single-photon emission computed tomography-computed tomography (SPECT/CT) imaging was performed to better characterize abnormal location. The significance of this serendipitous uptake is not clearly established. This finding could be due to altered distribution induced by the chemotherapy regimen and is not the result of intrinsic gallbladder disease.
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http://dx.doi.org/10.1097/RLU.0b013e31829f8e90DOI Listing
October 2013

Radiosynthesis and preclinical evaluation of 18F-F13714 as a fluorinated 5-HT1A receptor agonist radioligand for PET neuroimaging.

J Nucl Med 2012 Jun 10;53(6):969-76. Epub 2012 May 10.

University of Lyon 1, INSERM, CNRS, Lyon Neuroscience Research Center, Lyon, France.

Unlabelled: PET brain imaging of the serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) receptor has been widely used in clinical studies. Currently, only a few well-validated radiolabeled antagonist tracers are available for in vivo imaging of this central receptor. 5-HT(1A) receptors exist in high- and low-affinity states, depending on their coupling to G proteins. Agonists bind preferentially to receptors in the high-affinity state and thereby could provide a measure of functional 5-HT(1A) receptors. Therefore, it is of great interest to develop an (18)F-labeled full agonist 5-HT(1A) receptor radiotracer. In this study, we radiolabeled the high-affinity 5-HT(1A) receptor agonist (18)F-F13714 and investigated its potential as a PET tracer.

Methods: F13714 nitro precursor was synthesized and radiolabeled via a fluoronucleophilic substitution. In vitro binding assays were performed using established protocols. Radiopharmacologic evaluations included in vitro autoradiography in rat brain and PET scans on anesthetized cats.

Results: The chemical and radiochemical purities of (18)F-F13714 were greater than 98%. F13714 has a high affinity (0.1 nM) and selectivity for 5-HT(1A) receptors. In vitro (18)F-F13714 binding in rats was consistent with the known 5-HT(1A) receptors distribution (hippocampus and cortical areas) and was particularly high in the dorsal raphe. In vitro binding of (18)F-F13714 was blocked in a dose-dependent fashion by WAY100635, the prototypical 5-HT(1A) antagonist, and by the endogenous agonist, serotonin (5-HT). Addition of Gpp(NH)p also inhibited in vitro (18)F-F13714 binding, consistent with a preferential binding of the compound to G-protein-coupled receptors. Ex vivo tissue measurements in rat revealed an absence of brain radioactive metabolites. In vivo studies showed that the radiotracer entered the cat brain readily and displayed a preferential labeling of 5-HT(1A) receptors located in cingulate cortex. In vivo labeling was prevented by preinjection of WAY100635.

Conclusion: (18)F-F13714 is a radiofluorinated agonist that presents suitable characteristics for probing the high-affinity states of the 5-HT(1A) receptors in vitro and in vivo. Thus, it is a promising tool for investigation of 5-HT(1A) agonist binding in the living human brain.
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http://dx.doi.org/10.2967/jnumed.111.101212DOI Listing
June 2012

Small-animal positron emission tomography as a tool for neuropharmacology.

Trends Pharmacol Sci 2010 Sep 6;31(9):411-7. Epub 2010 Jul 6.

Neuropharmacology EAC CNRS 5006, Faculty of Pharmacy, University Lyon 1, University of Lyon, F-69373 Lyon, France.

Small-animal positron emission tomography (PET) is a preclinical imaging method that uses pharmacologically or biochemically active compounds labelled with short-lived positron-emitting radionuclides. This non-invasive nuclear medicine technique requiring animal-dedicated PET cameras (microPET) enables in vivo measurements of physiological processes, biochemical pathways and neurotransmitters. It therefore has a role in studying the pathophysiology and pharmacology of the brain. Moreover, there is increasing evidence that microPET imaging can accelerate drug development by revealing early information regarding biomarkers of pathophysiology or drug mechanisms and cerebral bioavailability. This review presents the potential contribution of microPET in basic neuropharmacology, illustrating its recent contributions and methodological specificities as well as highlighting its limits and constraints. In addition, we aim to encourage the use of PET molecular imaging in basic neuropharmacology to complement other preclinical approaches.
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http://dx.doi.org/10.1016/j.tips.2010.06.002DOI Listing
September 2010

Exposure of medical personnel to radiation during radionuclide therapy practices.

Nucl Med Commun 2008 Apr;29(4):405-10

Unité de Radiopharmacie, CHU Timone, Marseille, France.

Objectives: Radioisotopes that emit beta radiation are used for the treatment of hepatocellular carcinoma, of arthritic patients (radiosynovectomy) and treatment of bone metastases with, respectively, I-labelled lipiodol, colloidal citrate of Y or and Sm-labelled EDTMP. Radiation energy of these radioisotopes that emit beta or beta and gamma radiation (from 300 to 2000 keV) leads to an increase in radiation dose received by nuclear medicine staff. In this paper we focused on clinical and laboratory staff exposure during these types of metabolic radiation therapies.

Methods: Cylindrical LiF thermoluminescence dosimeters were used to measure radiation-related whole-body doses (WBDs) and finger doses of the clinical staff.

Results: Exposure of the two radiopharmacists and three nurses taking part in I-labelled lipiodol, Y-colloid and Sm-EDTMP therapies, for 12 months in succession, were 146 microSv and 750 microSv, respectively, considering WBD, and 14.6 mSv and 6.5 mSv, respectively, considering finger doses. Extrapolated annual exposures (six radiosynovectomies per year) for the rheumatologists were estimated to be 21 microSv (WBD) and 13.2 mSv (finger dose). Extrapolated annual WBDs and finger doses (25 I-labelled lipiodol treatments per year) for radiologists were estimated to 165 microSv and 3.8 microSv, respectively.

Conclusion: Fortunately, these doses were always lower than the limits reported in the European Directive EURATOM 96/29 05/13/1996 (WBD <20 mSv.year; finger dose: 500 mSv.year) but have to be added to those relative to other metabolic radiotherapies such as radioiodine treatments and new metabolic radiotherapies (Y-conjugated peptides or antibodies). Nevertheless, the global exposure of medical staff involved in all these clinical practices justifies dosimetry studies to validate protocols and radiation protection devices for each institution.
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http://dx.doi.org/10.1097/MNM.0b013e3282f4973aDOI Listing
April 2008

Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide.

J Clin Oncol 2007 Apr;25(12):1470-5

Unité de Neuro-Oncologie, Service de Neurochirurgie, Centre Hospitalier Universitaire Timone, Assistance Publique-Hôpitaux de Marseille, and Université de la Méditérranée, Faculté de Médecine de Marseille, Marseille, France.

Purpose: This phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy (RT) in patients with inoperable newly diagnosed glioblastoma.

Patients And Methods: Patients received temozolomide (150 mg/m2/d on days 1 to 7 and days 15 to 21 every 28 days; 7 days on/7 days off) for up to four cycles before conventional RT (2-Gy fractions to a total of 60 Gy) and for four cycles thereafter or until disease progression. The primary end point was tumor response. Tumor tissue from 25 patients was analyzed for O6-methylguanine-DNA methyltransferase (MGMT) expression.

Results: Twenty-nine patients with a median age of 60 years were treated, and 28 were assessable for response. Seven (24%) of 29 patients had a partial response, nine patients (31%) had stable disease, and 12 patients (41%) had progressive disease. Median progression-free survival (PFS) time was 3.8 months, and median overall survival (OS) time was 6.1 months. Patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). The most common grade 3 and 4 toxicities were thrombocytopenia (20%) and neutropenia (17%).

Conclusion: This dose-dense temozolomide regimen resulted in modest antitumor activity with an acceptable safety profile in the neoadjuvant setting, and expression of MGMT correlated with response to temozolomide. However, this treatment approach seems to be inferior to standard concomitant RT plus temozolomide.
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http://dx.doi.org/10.1200/JCO.2006.07.4807DOI Listing
April 2007

Reservoir cells no longer detectable after a heterologous SHIV challenge with the synthetic HIV-1 Tat Oyi vaccine.

Retrovirology 2006 Jan 27;3. Epub 2006 Jan 27.

UMR Univ, Med,/CNRS FRE 2737, Faculté de Pharmacie, Université de la Méditerranée, 27 Bd Jean Moulin, 13385 Marseille, France.

Background: Extra-cellular roles of Tat might be the main cause of maintenance of HIV-1 infected CD4 T cells or reservoir cells. We developed a synthetic vaccine based on a Tat variant of 101 residues called Tat Oyi, which was identified in HIV infected patients in Africa who did not progress to AIDS. We compared, using rabbits, different adjuvants authorized for human use to test on ELISA the recognition of Tat variants from the five main HIV-1 subtypes. A formulation was tested on macaques followed by a SHIV challenge with a European strain.

Results: Tat Oyi with Montanide or Calcium Phosphate gave rabbit sera able to recognize all Tat variants. Five on seven Tat Oyi vaccinated macaques showed a better control of viremia compared to control macaques and an increase of CD8 T cells was observed only on Tat Oyi vaccinated macaques. Reservoir cells were not detectable at 56 days post-challenge in all Tat Oyi vaccinated macaques but not in the controls.

Conclusion: The Tat Oyi vaccine should be efficient worldwide. No toxicity was observed on rabbits and macaques. We show in vivo that antibodies against Tat could restore the cellular immunity and make it possible the elimination of reservoir cells.
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http://dx.doi.org/10.1186/1742-4690-3-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1434768PMC
January 2006

HIV-1 Tat protein enhances microtubule polymerization.

Retrovirology 2005 Feb 3;2. Epub 2005 Feb 3.

UMR Univ, Med,/CNRS FRE 2737, Faculté de Pharmacie, Université de la Méditerranée, 27 Bd Jean Moulin, 13385 Marseille, France.

Background: HIV infection and progression to AIDS is characterized by the depletion of T cells, which could be due, in part, to apoptosis mediated by the extra-cellular HIV-encoded Tat protein as a consequence of Tat binding to tubulin. Microtubules are tubulin polymers that are essential for cell structure and division. Molecules that target microtubules induce apoptosis and are potent anti-cancer drugs. We studied the effect on tubulin polymerization of three Tat variants: Tat HxB2 and Tat Eli from patients who are rapid progressors (RP) and Tat Oyi from highly exposed but persistently seronegative (HEPS) patients. We compared the effect on tubulin polymerization of these Tat variants and peptides corresponding to different parts of the Tat sequence, with paclitaxel, an anti-cancer drug that targets microtubules.

Results: We show that Tat, and specifically, residues 38-72, directly enhance tubulin polymerization. We demonstrate that Tat could also directly trigger the mitochondrial pathway to induce T cell apoptosis, as shown in vitro by the release of cytochrome c from isolated mitochondria.

Conclusions: These results show that Tat directly acts on microtubule polymerization and provide insights into the mechanism of T cell apoptosis mediated by extra-cellular Tat.
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http://dx.doi.org/10.1186/1742-4690-2-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC549075PMC
February 2005